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Directed Synthesis of Peptides from -Amino Acid Esters at Metal Centers.

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4 &
Scheme 3. Reaction of 4 with chloromethylketene and subsequent lactonization. a) CH,CCI,COCI, Et,O, Zn/Cu, 40° C 7 h (82%); b) 48% HF, CH,CN,
20°C. 2 h (22a:65%, 22b:22%); c) AcOH, Zn, llO"C, 1 h (23a:19%, 23b:
53%): d)nBu,SnH, toluene, hv, -78°C. 1.5 h (89%); for further conditions
see text.
This novel, "intermolecular" ketene Claisen rearrangement is characterized not only by its excellent chemoselectivity but also by its excellent 1,2-syn selectivity (ca. 20:l). By
choice of suitably substituted precursors, such as 8 or 12, this
reaction offers a route to optically active y-butyrolactones, a
class of substances of use in numerous natural product syntheses.[231
[9] E. J. Corey, A. Venkateswarlu, 1.Am. Chem. Soc. 94 (1972) 6190.
[lo] E. Winterfeldt, Synthesis 1975, 617.
[ l l ] R. P. Volante, Tetrahedron Left. 22 (1981) 3119.
(121 T. Rosen, M. Watanabe, C . H. Heathcock, J. Org. Chem. 49 (1984) 3657.
[13] a) M. J. Miller, J. S. Bajwa. P. G. Mattingly, K. Peterson, J. Org. Chem. 47
(1982) 4928; b) M. J. Smith, Tetrahedron Lett. 30 (1989) 313.
[14] D. R. Morton, J. L. Thompson, J. Org. Chem. 43 (1978) 2102.
[15] S.-J. Shiuey, J. J. Partridge, M. R. Uskokovic, J. Org. Chem. 53 (1988)
[16] S. Hatakeyama, K. Saijo, S. Takano, Tefrahedron Letf. 26 (1985) 865.
1171 J. K. Cha, S. C. Lewis, Tetrahedron Lefr. 25 (1984) 5263.
[IS] M. ChCrest, H. Felkin, N. Prudent, Tetrahedron Leu. 1968, 2199; K. N.
Houk, S. R. Moses, Y.-D. Wu, N. G. Rondan, V. Jager, R. Schohe. F. R.
Fronczek, J. Am. Chem. Soc. 106 (1984) 3880.
1191 S. D. Kahn, W. J. Hehre. J. Org. Chem. 53 (1988) 301.
(201 The NMR data for 17 are identical with published values [16].
[21] The Zisomer of the sulfide 4 afforded exclusivelycyclobutanone under the
rearrangement conditions.
[22] Methylation of 17,as described by Fleming et al. (I. Fleming, I. Paterson,
Synthesis 1979, 736) led to isomer 23a and thereby allowed the absolute
configuration of the lactones 23 to be confirmed.
[23] C . W. Jefford, A. W. Sledeski, J. Boukouvalas, Helv. Chim. Actu 72 (1989)
1362; K. Koseki, T. Ebata, H. Kawakami, H. Matsushita. Y. Naoi, K. Itoh,
Heterocycles 31 (1990) 423.
Experimental Procedure
One-pot procedure for the synthesis of a$-unsaturated esters 2 and 6 [6 b]: The
a-doxy ester (60 mmol), dissolved in 60 mL of dry hexane at - 78°C. was
treated dropwise over 30 min with 65 mL of a 1 M solution of DIBAH in hexane
under argon. After 1 h, methoxycarbonylmethylene(tripheny1)phosphorane
(60 mmol) in 40 mL of TH F and 50 mL of CH,CI, was added. The reaction
mixture was then allowed to warm over 1 h to room temperature, poured into
ice water, and extracted with diethyl ether. The organic phase was washed with
a saturated aqueous NaCl solution and the E / Z mixture separated by chromatography on silica gel.
Mitsunobu variant for the synthesis of the allyl thioacetate: Freshly distilled
DEAD (20 mmol) was injected into a solution of triphenylphosphane
(20 mmol) in 20 mL of dry T HF at 0°C under argon. After 40 min, allyl alcohol
(10 mmol) and freshly distilled thioacetic acid (20 mmol), each dissolved in
5 mL of THF, were successively added dropwise. Monitoring by thin layer
chromatography revealed that the reaction was over after about 1 h. Pentane
was added and the mixture was filtered through silica gel with pentane/ether
(1 :1) as eluent. After removal of the solvent, the thioester was chromatographed or purified by distillation.
Ketene Claisen rearrangement of allyl thioether: Ally1 thioether (1.5 mmol) and
about 15 mmol of Zn/Cu alloy [4] were placed in 15 mL of vigorously stirred
ether under argon and the mixture was heated to reflux. A solution of 3 mmol
of freshly distilled trichloroacetyl chloride in 5 mL ofether was added dropwise
to the solution over 4 h by means of a syringe pump (7 h infusion for the
generation of chloromethylketene from 2,2-dichloropropionyI chloride). After
cooling, the reaction solution was decanted from the residue. Purification of the
thioester was accomplished by chromatography on silica gel.
Received: March 7, 1991;
Revised version: August 19, 1991 [Z 4480 IE]
German version: Angew. Chem. 103 (1991) 1533
[l] L. Claisen, Chem. Ber. 45 (1912) 3157.
[2] a) R. Hill. Asymmetric Synfh. 3 B (1984) 503, and references cited therein;
b) F. E. Ziegler. Chem. Rev. 88 (1988) 1423.
[3] R. E. Ireland, P. G. M. Wuts, B. Ernst,J. Am. Chem. SOC.103(1981) 3205;
R. E. Ireland. R. C. Anderson. R. Badoud, B. J. Fitzsimmons, G. J. McGarvey, S. Thaisrivongs, C. S. Wilcox, ibid. 105 (1983) 1988.
[4] R. Malherbe, D. BelluS, Helv. Chim. Acfa61(1978) 3096; R. Malherbe, G.
Rist. D. BelluS, Org. Chem. 48 (1983) 860; G. Rosini, G. G. Spineti, E.
Foresti. G. Pradella, ibid. 46 (1981) 2228; E. Vedejs, R. A. Buchanan, ibid.
49 ( 1984) 1840.
[5] R. Ohrlein. R. Jeschke, B. Ernst, D. BelluS. Tetrahedron Left. 30 (1989)
[6] a) S. K . Massad, L. D. Hawkins, D. C . Baker, J. Org. Chem. 48 (1983)
5180. b) A. Krief, W. Dumont, P. Pasau, Tetrahedron L e f t .29 (1988) 1079;
c) R. Annunziata, M. Cinquini, F. Cozzi, G. Dondio, L. Raimondi, Tetraheriron 43 (1987) 2369.
[7] J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 34 (1969) 2543.
- 4.0 (c = 1, CHCI,); 8: [a];' - 3.7 ( c = 0.75, CHCI,); 12:[a];'
[8] 4:
-7.6 ( c = 1, CHCI,); 14: [#' - 27.4 ( c = 0.9, CHCI,); 15: [a];' - 23.5
( c = 1.6. CHCI,): 16: [a];' -7.6 ( c = 1.2, CHCI,); 21: [a];' - 39.4
(c = 0.5. CHCI,).
Angew. Chem. Int. Ed. Engl. 30 (1991) No. 11
Directed Synthesis of Peptides from a-Amino
Acid Esters at Metal Centers **
By Wolfgang Beck* and Roland Kramer
Dedicated to Professor Viktor Gutmann on the occasion
of his 70th birthday
The first directed synthesis of peptides from nonactivated
a-amino acid esters at a metal center was accomplished with
cobalt(Ii1) amine complexes.['] The cobalt atom acts as an
amino protecting group and, at the same time, activates the
carboxyl group."] However, the preparation of oligopeptides by this route is relatively laborious, since the peptide
has to be liberated from the metal and isolated before it is
allowed to react with the next a-amino acid ester complex of
Several metal salts, particularly those of copper(n), catalyze the formation of peptides (up to tetrapeptides) from
a-amino acid
Different a-amino acid esters, however, cannot be linked in a defined sequence; instead, a mixture of the corresponding peptides is ~ b t a i n e d . [ ~An
. ~ inter]
esting model for the prebiotic formation of peptides is the
recently described Cu"-catalyzed synthesis of peptides from
a-amino acids in aqueous NaCl solution.[']
We have now found a way to extend metal-coordinated
peptide esters from the amino terminus in a controlled manner. In the course of our work on chiral organometallic compounds containing a-amino acids,[61 we obtained the
diglycine ester complexes 1 and 2, in which the amide N atom
is deprotonated.
These chelate complexes react with a-amino acid esters
such as Gly-OEt, L-Ala-OMe, L-Leu-OMe, L-Asp-(OMe), ,
and L-Ser-OMe in the presence of triethylamine at 20 "C to
give the corresponding tripeptide ester complexes 3 and 4,
[*] Prof. Dr. W Beck, DipLChem. R. Kramer
Institut fur Anorganische Chemie der Universitat
Meiserstrasse 1, W-8000 Munchen 2 (FRG)
[**I Metal Complexes Containing Biologically Important Ligands, Part 62.
This work was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We thank Professor Dr. E. Wiinsch,
Max-Planck-Institut fur Biochemie, Martinsried, for amino acid analyses
and for valuable and encouraging discussions. Part 61: 1161.
Verlagsgesellschaf~mbH. W-6940 Weinheim, 1991
respectively, in yields of 70-90 % (crystalline p r o d ~ c t s ) . ~ ' ~
Complex 3 b was also prepared in a one-pot reaction from
[{Cp*RhC12}z] (Cp* = q5-C,Me5), Gly-Gly-OMe .HC1,
and Ala-OMe with Na,CO, as base (80% yield). Treatment
of complexes 3 b, c (see Experimental Procedure) with 0.2 N
methanolic HCI solution liberated the tripeptide esters
L-Ala-Gly-Gly-OMe . HCl and L-Leu-Gly-Gly-OEt .HCI,
respectively, which were then isolated; [{Cp*RhCl,},] was
thereby re-formed. The tripeptides in 3b, c are formed with-
la M-Rh, R=Me
Ib M-Rh, R-El
2 M-lr, R-El
1. 2
M R'
3a Rh H
b Rh Me
4a ir H
b Ir CH20H
out almost any racemization. For comparison, 3a, which cannot be isolated in pure form, was synthesized directly from
Gly-Gly-Gly-OEt and [{ Cp*RhCI,},] and characterized by
X-ray structure analysis.['I The tetrapeptide ester complex 5
is formed via a triglycine methyl ester complex as intermediate when Gly-OEt and Ser-OMe are added successively to 1a.
a) 15 Gly-OEt.21 h
bl 15 Ser-OMe.25 h
NEl3, MeOH. ZO'C
Further peptide ester complexes are formed as side products (ca. 15%) in these reactions. Independently, 5 was obtained from [Cp*(Cl)Rh(Gly-Gly-Gly-OMe- H ')] and
Ser-OMe in the presence of NEt, and its structure was determined by X-ray analysis.['I The principle illustrated in
Scheme 1 should allow still longer peptide chains to be constructed at the complex in a one-pot procedure.
Scheme 1 . AS = a-amino acid building block, AS'
[MI = metal complex fragment.
C-terminal amino acid,
A template reaction is plausible for the mechanism of peptide formation. The synthesis of the tripeptide at the metal
center affords complexes with three accessible (here, facially
arranged) coordination sites. The crucial step is a nucleophilic attack of the coordinated amino anion in B on the
carbonyl group of the N-coordinated amino acid ester. Yamada et al. have suggested such a step for peptide formation
at CU".[~'~
The base serves only as catalyst. The intermediacy
of C (M = Rh, R = Et, R = CH,CO,Me) could be established by reaction of 1 b with asparagine dimethyl ester and
sodium methoxide instead of NEt, . The complex [Cp*Rh{L1468
Verlagsgesellschafi mbH, W-6940 Weinheim, 1991
Asp@-0Me)-Gly-Gly-OEt - 2 H']] (6)was characterized
by crystal structure
it contains an unusual structural element, a bridgehead peptide N atom surrounded in a
pyramidal fashion (sum of angles at N atom: 346.l0).["l
Of particular interest is the question whether optically
active dipeptide ester complexes preferentially incorporate
only one enantiomer of an a-amino acid ester present as
a racemate. The reactions of [Cp*(Cl)Rh(L-Ala-GlyOMe - H ')] with D,L-Leu-OMe and D,L-Ser-OMe indicate
that the tripeptide esters L-Leu-L-Ala-Gly-OMeand L-Ser-LAla-Gly-OMe are formed somewhat faster at the complex
than the corresponding diastereoisomers D-Leu-L-Ala-GlyOMe and D-Ser-L-Ala-Gly-OMe, respectively.
Experimental Procedure
NEt, (1.00 mmol, 139 p L ) was added to a solution of 1a (0.20 mmol, 84 mg;
prepared from [{Cp*RhCI,},] [12], Gly-Gly-OMe . HCI, and two equivalents
of NaOMe in methanol) and L-Leu-OMe (0.21 mmol, 32 pL) in 5 mL of absolute methanol. The reaction mixture was stirred for 15 h at 20°C and then
concentrated to about 0.5 mL. Addition of 20 mL ofether and 30 mL of hexane
resulted in precipitation of the orange complex. The isolated and dried complex
3c (yield 92%) was dissolved in 5 mL of0.2 N methanolic HCI and the solution
was then concentrated to about 1.5 mL and kept at -78°C for 2h. The precipitate of [{Cp*RhCI,},] was filtered off and the filtrate was concentrated to
about 0.5 mL and treated with 50 mL of ether. The resulting solution was
cooled with liquid nitrogen until it began to solidify and then allowed to warm
to room temperature with stirring. The precipitated tripeptide ester hydrochloride was centrifuged, washed with 30 mL of CHCl,/hexane (l/l), and reprecipitated from methanol/ether (yield 61 YObased on la). 'H NMR of L-Leu-GlyGly-OMe . HCI [I 31 (400 MHz, CD,OD, 22 "C,TMS): S = 3.92 (m, 1 H, partly
overlapped; Leu-Ha), 1.7 (m, 3H; CH-CH,, CH(CH,),), 1.01 (m, 6 H ;
CH(CH,),), 3.92, 4.05 (d, 'J(H,H) = 16.3 Hz, 1 H; NHCOCH,, diastereotopic), 3.98 (s, 2 H ; CH,CO,CH,), 3.72 (s, 3 H ; CO,CH,).
Amino acid analysis [14]: Leu,,,Gly, . TLC (nBuOH/glacial acetic acid/water
4/1/1; silica gel): R, = 0.47. Gas-chromatographic racemate test [IS]: 1.5%
o-Leu-OMe. Racemate test for L-Ala-Gly-Gly-OEt HCI isolated from 3 b :
1 .0 % D-Ala.
The reaction of [Cp*Rh(CI)(L-Ala-Gly-OMe. HCI)] with D,L-Leu-OMe or D,LSer-OH was carried out analogously to the preparation 3c. The reaction times
were chosen so that only a small amount of the added amino acid ester reacted.
After 3.5 and 2 h, respectively, the complexes were isolated and treated with
0.2 N methanolic HCI solution. In the liberated peptide esters (nonreacted serine methyl ester could not be separated quantitatively from the complex),
amino acid ratios of Leu,,,Ala,,,,Gly,,,,
and Ser,,,,Ala,,,Gly,,,,,
respectively, and L-proportions of L-Leu (52.3 %)/L-Ala (99.1 %) and L-Ser (61.3 %)/
L-Ala (99.1 %), respectively, were determined.
Received: April 25, 1991 [Z 4594 IE]
German version: Angew. G e m . 103 (1991) 1492
[I] D. A. Buckingham, L. G. Marzilli, A. M. Sargeson, J Am. Chem. Soc. 89
(1967) 2772; J. P. Collman, E. Kimura, ibid. 89 (1967) 6096; P. A. Sutton,
D. A. Buckingham, Acc. Chem. Res. 20 (1987) 357.
[2] D. R. Knighton, D. R. K. Harding, M. J. Friar, W. S. Hancock, G. D.
Reynolds, C. R. Clark, R. F. Tasker, D. A. Buckingham, J Am. Chem.
Soc. 103 (1981) 7025.
0570-0833i91jlill-1468 $3.S0+.2S/O
Angew. Chem. In!. Ed. Engl. 30 (1991) No. 11
[3] a) S. Yamada, M. Wagatsuma, Y. Takeuchi, S. Terashima, Chem. Pharm.
Bull. 19 (1971) 2380; S. Yamada, S. Terashima, M. Wagatsuma, Tetrahedron Lett. 1970,1501 ; b) S. Terashima, M. Wagatsuma, S. Yamada, Tetrahedron 29 (1973) 1487; c) M. Wagatsuma, s. Terashima, S . Yamada, ibid.
29 (1973) 1497.
[4] H. Schmidt. Diplomarbeit, Universitat Miinchen 1984; M. Maurus, Diplomurbeit, Universitat Miinchen 1991.
[5] M. G. Schwendinger, B. M. Rode, Anal. Sri. 5 (1989) 411; B. M. Rode,
Spektrum Wiss. 1991, No. 3, p. 26; B. M. Rode, M. G. Schwendinger,
Origins Life Evol. Biosphere 20 (1990) 401.
161 R. Kramer, K. Polborn, H. Wanjek, 1. Zahn, W. Beck, Chem. Ber. 123
(1990) 767; W. Beck, W. Petri, J Organornet. Chem. 127 (1977) C40. Cf.
also D. Carmona, A. Mendoza, F. J. Lahoz, L. A. Oro, M. P. Lamata, E.
San Jose, ibid. 396 (1990) C 17.
171 a ) I n 3-5 (CD,OD solution, 20"C), the epimerization at the metal atom is
fast on the NMR time scale. For the complexes [Cp*(Cl)M(L-amino acid
anion)], M = Rh, Ir, on the other hand, the expected diastereoisomers
(SJ,. S,S,) were detected by NMR spectroscopy [6]; b) We found that
the corresponding complexes with coordinated glycinamide and glycinate
as bidentate ligands also react with a-amino acid esters according to this
[8] B. Wagner, R. Kramer, W. Beck, unpublished. The synthesis and structure
- H ')I
of a comparable complex, [(t~~-C,H,)(Cl)Ru(Gly-Gly-Gly-0H
has been described: W. S . Sheldrick, S . Heeb, J. Orgunomet. Chem. 377
(1989) 357.
[9] K. H. Siinkel, R. Kramer, W. Beck, unpublished.
[lo] C. Robl. R. Kramer, W. Beck, unpublished.
[ll] As in free peptides, the coordinated, deprotonated peptide N atoms here
usually show planar environments: H. C. Freeman, Adv. Protein Chem. 22
(1967) 257; H. Sigel, R. B. Martin, Chem. Rev. 82 385; S. H. Laurie in G.
Wilkinson, R. D. Gillard, J. A. McCleverty (Eds.): Comprehensive Coordination Chemiswy, Vol. 2, Pergamon, Oxford 1987, p. 759.
[12] J. W. Kang, K. Moseley, P. M. Maitlis, J. Am. Chem. Soc. 91 (1969) 5970;
B. L. Booth, R. N. Haszeldine, M. Hill, J. Chem. Sor. A f 9 6 9 , 1299.
[I31 The 'H NMR data are similar to those of Leu-Gly-GlyH . HCI. Cf. M.
Anteunis, R. Callens, J Magn. Reson. 15 (1974) 317.
[14] Hydrolysis with half-concentrated hydrochloric acid; amino acid analyzer
Biotronic LC 6001.
[I 51 The racernate test was performed with the N-(pentafluoropropiony1)amino acid propyl esters on Chirasil-Val@(Carlo Erba HR GC 4160): H.
Frank, G. J. Nicholson, E. Bayer, J. Chromatogr. 167(1978) 187.
[I61 1. Zahn, K. Polborn, W. Beck, J. Organornet. Chem. 412 (1991) 397.
Synthesis of Ethenyl( pheny1)iodonium Triflate,
[H2C=CHIPh][0SO2CFJ, and Its Application as
a Parent Vinyl Cation Equivalent **
By Peter Stang* and Jorg Ullmann
Dedicated to Professor Michael Hanack
on the occasion of his 60th birthday
Vinylations are well recognized and widely employed in
organic chemistry. However, most known vinylating agents
are nucleophilic, such as vinylmetals of the first and second
main-group elements as well as vinylsilanes and -stannanes.['l
Vinylations have also been carried out with acetylenel2Iand
by metal-catalyzed
However, there are only few
examples for the electrophilic introduction of the parent vinyl moiety (e.g., vinyl ethers, acetates, and halides"]).
Ethenyl(pheny1)iodonium triflate (3) is a novel electrophilic
vinylating agent with promising applications in vinylation
reactions that are not covered by the known reagents mentioned above. For example, 3 may be employed to synthesize
the hitherto unknown parent vinyl triflate (4))"l a possible
precursor for the generation of the parent vinyl cation151as
[*I Prof. Dr. P. J. Stang, Dr. Jorg Ullmann
Department of Chemistry, University of Utah
Salt Lake City, UT 84112 (USA)
[**I This work was supported by the National Cancer Institute of the National
Institutes of Health (2ROCA16903). J U . thanks the Alexander von Humboldt Foundation for the award o f a Feodor Lynen Fellowship.
Angen. Chem. Int. Ed. Engl. 30 (1991) No. I 1
well as for metal-catalyzed vinylic couplings.16]Compound 3
should also undergo oxidative addition to organometallic
substrates, serving formally as a vinyl cation equivalent.
Such a synthesis complements the more traditional methods
for the introduction of the o-bonded parent vinyl substituent
into organometallic complexes, mainly the use of vinylmagnesium bromide in displacement reaction^^'^ and the equili8]
bration of n-ethene complexes.r7a*
Phl(CN)OTf 2
H,C=CH -0Tf
Ph,P,,, I <,CO
C1' i .PPh,
5b, M = Ir
5a, M = R h
Salt 3 was obtained from tri-n-butyl(viny1)tin (1) and cyano(pheny1)iodonium triflate (2) in 75 % isolated yield.['.
The previously unknown parent vinyl triflate (4) was formed
from 3 by cleavage of the C-I bond in the presence of catalytic amounts of silver triflate. Isolation of 4 was possible
from benzonitrile by distilling 4 directly from the reaction
mixture (15 to 20% yield). Compound 4 is fully characterized. Noteworthy is the 13C NMR spectrum, where the signals of the vinyl carbons of 4 have changed positions with
respect to 3 (3, hCH2= 133.4, 6,, = 109.5; 4, 6, = 106.4,
6, = 143.5).
Iodonium salt 3 is also a strong electrophilic substrate in
organometallic reactions. Treatment of Vaska's complex or
its rhodium analogue with 3 yields the new octahedral hexacoordinate rhodium and iridium species 5a, b in 84 and 75 YO
yield, respectively. The IR spectrum reveals a strong CO
vibration at f = 2063 cm-' for 5 a and at J = 2088 cm-' for
5b. In the far-infrared region of 5a, an Ir-CI stretch at J =
307 cm-' indicates a trans arrangement between the CI and
CO ligands.['21 Likewise, the trans relationship of the phosphane ligands and the octahedral symmetry is confirmed in
the 31PNMR spectrum by the typical high-field position of
the Rh doublet (6 = 15.1) for 5 b and the singlet (6 = - 8.3)
for 5a.
The introduction of the parent vinyl substituent into organometallic substrates via 3 constitutes a significant change in
methodology. Rather than vinylmagnesium bromide reacting as a nuclephile due to the carbanionic character of the
vinyl substituent, 3 shows an umpolung of the vinyl reactivity, making it employable as an electrophile in oxidative
additions. Traditionally, oxidative additions are well established as a method for the introduction of alkyl substituents," 31 but could not be used for vinylations owing to
the unreactivity of simple vinyl
Other applications of 3 are under investigation (e.g., cycloadditions). Preliminary results show that 3 reacts with
cyclopentadiene. Isolation of the expected product, however,
is not possible owing to the thermal instability of alkyliodonium salts.
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